Neoadjuvant Chemo Reduces 2-Year Risk for Residual, Recurrent Disease by 28% in Colon Cancer

Six weeks of preoperative oxaliplatin-fluoropyrimidine chemotherapy did not increase perioperative morbidity in patients with radiologically staged T3-4, N0-2, M0 colon cancer, according to findings from the international phase 2/3 FOxTROT trial (NCT00647530). Furthermore, treatment with neoadjuvant chemotherapy (NAC) resulted in significant histopathologic downstaging, fewer incomplete resections, and better 2-year disease control.

Patients colon cancer were randomly assigned to 6 weeks of preoperative oxaliplatin-fluoropyrimidine plus 18 weeks postoperative treatment (n = 699) or 24 weeks adjuvant chemotherapy (AC; n = 354). More than 98% of patients in both groups underwent surgery.

Patients in the NAC group saw marked T and N downstaging and histologic tumor regression (all P < .001) and were more likely to have histopathologically complete resection than the control group (94% vs 89%; P < .001). Patients in the NAC arm were also less likely to have residual or recurrent disease within 2 years (16.9% vs 21.5%), corresponding with a 28% lower recurrence rate for NAC compared with the control (rate ratio [RR], 0.72; 95% CI, 0.54-0.98; P = .037).

The proportional reductions in colon cancer–specific mortality (RR, 0.74; 95% CI, 0.52-1.05, P = .095) and all-cause mortality (RR, 0.76; 95% CI, 0.55-1.06; P = .104) were of similar magnitude but did not reach statistical significance.

Surgery followed by adjuvant oxaliplatin-fluoropyrimidine chemotherapy is the standard of care for moderate- to high-risk colon cancer. However, 20% to 30% of patients develop recurrent, often incurable, disease despite AC. Previous data have found that NAC substantially improved outcomes in other gastrointestinal cancers, and investigators in FOxTROT hypothesized that preoperative treatment might have advantages over postoperative AC in colon cancer.

Tumor regression correlated strongly with freedom from recurrence. Notably, the addition of panitumumab (Vectibix) did not enhance the benefit from NAC (RR = 0.67; 95% CI, 0.36-1.23; P = .19). Little benefit from NAC was seen in mismatch repair–deficient tumors.

Eligibility criteria included biopsy-confirmed colon cancer, CT-predicted T3-4 with extramural extension of at least 5 mm (equal to or greater than 1 mm after the pilot phase), M0, and being fit for both surgery and chemotherapy. Patients with bowel obstruction were eligible if first defunctioned with a stoma.

Investigators randomly assigned patients 2:1 to NAC followed by surgery and AC or surgery followed by AC. Patients with RAS wild-type tumors could also be randomly assigned 1:1 receive panitumumab (n = 137) or not (n = 133) during NAC.

Investigators administered treatment using a modified FOLFOX schedule: 85 mg/m2 oxaliplatin plus 175 mg l-folinic acid and 400 mg/m² fluorouracil repeated once every 2 weeks. Patients in the NAC arm received surgery 4 to 6 weeks following the completion of NAC. Patients in the control arm received surgery as soon as possible. Dose reductions, treatment delays, and early cessation for toxicity were permissible as in routine practice.

The median patient age was 63 years. At baseline, CT scan detected T4 disease in 268 (25%) patients and lymph-node involvement in 792 (75%). The median follow-up was 3.1 years (interquartile range, 2.5-4.9).

Investigators found a strong correlation between risk for recurrence and grade of histologic regression. At 5 years, the recurrence rate was 30% among those with no regression, falling to 22% with mild regression, 13% with moderate, 7% in marked, and 0% with complete

regression. Among patients in the control group, the recurrence rate for tumors deemed to have mild (17%) or moderate (1%) regression was actual higher than in tumors with no regression (RR, 1.66; 95% CI, 0.91-3.03; P = .102).

Investigators observed serious perioperative complications following NAC more often than after immediate surgery. Following NAC, investigators observed fewer anastomotic leaks or abdominal abscesses (4.7% vs 7.4%; RR, 0.63; 95% CI, 0.38-1.04; P = .072), fewer emergency reoperations (4.3% vs 7.1%;RR, 0.60; 95% CI, 35-1.00; P = .050), and fewer suffered complications prolonging hospital stay (11.6% vs 14.3%; RR, 0.81; 0.58-1.13; P = .21) compared with the control arm. Furthermore, there were fewer deaths from non–colon cancer causes without recorded recurrence within 2 years from random assignment in the NAC group compared with the control (0.6% vs 1.7%; P = .076).

Reference

Morton D, Seymour M, Magill L, et al. Preoperative chemotherapy for operable colon cancer: mature results of an international randomized controlled trial. J Clin Oncol. Published online January 19, 2023. doi:10.1200/JCO.22.00046